Support is requested for a Keystone Symposia meeting entitled Modern Phenotypic Drug Discovery: Defining the Path Forward, organized by Jonathan A. Lee, Ellen L. Berg and Eugene C. Butcher. The meeting will be held in Big Sky, Montana from April 2-6, 2016. Innovation and productivity in pharmaceutical drug discovery have been below expectations. Surprisingly, more first-in-class small molecule drugs approved by the FDA (1999-2008) were identified by functional approaches reminiscent of pre-genomics pharmacology (phenotypic drug discovery) than by contemporary molecular targeted strategies. This observation, and the unexpected difficulties of target validation, have diminished the impact of the genomics revolution and are arguably associated with the decline in innovation and productivity of pharmaceutical research. As a result, pharmaceutical researchers have begun to reevaluate the Molecular Mindset which has dominated our collective drug-hunting culture, and explore modern approaches to phenotypic screening. However, there is currently no single scientific forum where scientists from pharma, biotech, academia and instrument/service providers can meet and discuss strategies/issues related to phenotypic drug discovery (PDD). In part, this is because PDD encompasses multiple therapeutic areas and involves diverse disciplines including drug discovery, chemistry, cell biology, stem cell biology, systems biology, genomics, bioengineering and informatics. This Keystone Symposia meeting will uniquely provide this interdisciplinary environment and is a particularly attractive venue given the increasing role of academia in drug discovery research. The conference will be a forum for the global PDD research community in which scientists from diverse institutions and scientific disciplines can meet to share/discuss/debate topics related to advantages/disadvantages of PDD and how PDD can complement targeted approaches. Significantly, the conference will provide a much needed forum for the growing interest in PDD, and can conceivably become the cornerstone of the global scientific movement for the reintroduction of functional biology/physiology-driven pharmaceutical research. NCATS and PDD have very similar scientific objectives and philosophical approaches. Specifically the long term objective of both endeavors is to enhance the efficiency of drug discovery and to deliver novel therapeutics for unmet medical needs in a therapeutic area agnostic manner. Both efforts are strong proponents of multi-disciplinary collaboration, integrative analysis of diverse data sets, and the incorporatin of new technologies and scientific approaches. Both NCATS and PDD seek to modernize drug discovery and deliver new medicines through scientific innovation and cross functional collaboration.